1-201110216-G-C

Position:

chr1-201110216-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000069.3(CACNA1S):c.206C>G(p.Ala69Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0464 in 1,614,088 control chromosomes in the GnomAD database, including 2,004 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A69D) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.035 ( 135 hom., cov: 33)

Exomes 𝑓: 0.048 ( 1869 hom. )

Consequence

CACNA1S
NM_000069.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: 7.65

Variant links:

Genes affected

CACNA1S (HGNC:1397): (calcium voltage-gated channel subunit alpha1 S) This gene encodes one of the five subunits of the slowly inactivating L-type voltage-dependent calcium channel in skeletal muscle cells. Mutations in this gene have been associated with hypokalemic periodic paralysis, thyrotoxic periodic paralysis and malignant hyperthermia susceptibility. [provided by RefSeq, Jul 2008]

CACNA1S links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009147704).

BP6

Variant 1-201110216-G-C is Benign according to our data. Variant chr1-201110216-G-C is described in ClinVar as [Benign]. Clinvar id is 254811.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-201110216-G-C is described in Lovd as [Benign]. Variant chr1-201110216-G-C is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0502 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1S	NM_000069.3 linkuse as main transcript	c.206C>G	p.Ala69Gly	missense_variant	2/44	ENST00000362061.4	NP_000060.2	Q13698
CACNA1S	XM_005245478.4 linkuse as main transcript	c.206C>G	p.Ala69Gly	missense_variant	2/43		XP_005245535.1	B1ALM3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1S	ENST00000362061.4 linkuse as main transcript	c.206C>G	p.Ala69Gly	missense_variant	2/44	1	NM_000069.3	ENSP00000355192.3		Q13698

Frequencies

GnomAD3 genomes

AF:

0.0350

AC:

5326

AN:

152216

Hom.:

134

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0101

Gnomad AMI

AF:

0.00658

Gnomad AMR

AF:

0.0375

Gnomad ASJ

AF:

0.0112

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0391

Gnomad FIN

AF:

0.0463

Gnomad MID

AF:

0.0411

Gnomad NFE

AF:

0.0516

Gnomad OTH

AF:

0.0397

GnomAD3 exomes

AF:

0.0362

AC:

9110

AN:

251420

Hom.:

225

AF XY:

0.0383

AC XY:

5201

AN XY:

135890

show subpopulations

Gnomad AFR exome

AF:

0.00898

Gnomad AMR exome

AF:

0.0200

Gnomad ASJ exome

AF:

0.00973

Gnomad EAS exome

AF:

0.000217

Gnomad SAS exome

AF:

0.0414

Gnomad FIN exome

AF:

0.0439

Gnomad NFE exome

AF:

0.0505

Gnomad OTH exome

AF:

0.0349

GnomAD4 exome

AF:

0.0476

AC:

69613

AN:

1461754

Hom.:

1869

Cov.:

AF XY:

0.0475

AC XY:

34522

AN XY:

727176

show subpopulations

Gnomad4 AFR exome

AF:

0.00777

Gnomad4 AMR exome

AF:

0.0203

Gnomad4 ASJ exome

AF:

0.0105

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.0413

Gnomad4 FIN exome

AF:

0.0447

Gnomad4 NFE exome

AF:

0.0535

Gnomad4 OTH exome

AF:

0.0427

GnomAD4 genome

AF:

0.0350

AC:

5326

AN:

152334

Hom.:

135

Cov.:

AF XY:

0.0344

AC XY:

2564

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.0100

Gnomad4 AMR

AF:

0.0374

Gnomad4 ASJ

AF:

0.0112

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.0396

Gnomad4 FIN

AF:

0.0463

Gnomad4 NFE

AF:

0.0516

Gnomad4 OTH

AF:

0.0393

Alfa

AF:

0.0450

Hom.:

123

Bravo

AF:

0.0324

TwinsUK

AF:

0.0556

AC:

206

ALSPAC

AF:

0.0498

AC:

192

ESP6500AA

AF:

0.0102

AC:

ESP6500EA

AF:

0.0541

AC:

465

ExAC

AF:

0.0372

AC:

4510

Asia WGS

AF:

0.0140

AC:

AN:

3478

EpiCase

AF:

0.0520

EpiControl

AF:

0.0484

ClinVar

Significance: Benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 23, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 07, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Malignant hyperthermia, susceptibility to, 5

Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 05, 2018	- -
Benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	- -

Hypokalemic periodic paralysis, type 1

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Congenital myopathy 18

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 2023

- -

Thyrotoxic periodic paralysis, susceptibility to, 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 2023

- -

Malignant hyperthermia, susceptibility to, 5;C3714580:Hypokalemic periodic paralysis, type 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.49

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.30

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.64

D;D

Eigen

Pathogenic

0.71

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.84

T;T

MetaRNN

Benign

0.0091

T;T

MetaSVM

Benign

-0.41

MutationAssessor

Uncertain

2.5

.;M

PrimateAI

Uncertain

0.69

PROVEAN

Uncertain

-2.5

N;D

REVEL

Uncertain

0.37

Sift

Benign

0.17

T;T

Sift4G

Benign

0.22

T;T

Polyphen

0.87

.;P

Vest4

0.26

MPC

0.40

ClinPred

0.026

GERP RS

4.9

Varity_R

0.34

gMVP

0.72

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over